Diabetes, which is a metabolic disorder caused by plural factors, is roughly classified into Type I diabetes caused by failure of insulin secretion and Type II diabetes resulting from decline of insulin sensitivity in peripheral tissues. A rapid increase of Type II diabetes has been recognized in recent years, attributable to environmental factors such as obesity and hyperphagia as background factors. Diabetes prevalence rate in the world is estimated to be 5%.
Insulin and sulfonylurea agents are frequently used for medicinal treatments of diabetes. However, insulin and sulfonylurea agents induce hypoglycemia as a side effect and sulfonylurea agents also induce secondary pancreatic failure because of exhaustion of pancreas. Biguanide agents improve the insulin sensitivity and slightly normalize hyperglycemia, however, the agents have possibility to induce lactic acidosis. A thiazolidinedione type therapeutic medicine for diabetes, which has been recently developed, has an improving effect on insulin resistance in periphery (Expert Opinion on Investigational Drugs, 9, pp1347–1361, 2000), and is considered to achieve suitable blood glucose control without causing hypoglycemia. However, the medicine is reported to have side effects such as serious hepatic disorder. Therefore, a non-thiazolidinedione type medicine for improving insulin resistance is desired.
As a non-thiazolidinedione type compound, 2,2-dichloroalkanecarboxylic acid compound is known to lower a blood glucose level in a diabetes-model animal, and also exhibit decreasing actions of plasma insulin and plasma triglycerides (European Journal of Medicinal Chemistry, 33, pp775–787, 1998). Hyperinsulinemia suggests the presence of insulin resistance, and hyperlipemia, as a dysfunction of lipid metabolism with diabetes, is considered to be a risk factor of atherosclerosis. Therefore, improvements of the above symptoms are important for preventive and/or therapeutic treatment of diabetes and complications of diabetes.
For example, the following Compound A exert anti-diabetes actions in various animal models (Compound 3e described in Eur. J. Med. Chem., 33, pp.775–787, 1998; Metabolism, 48, pp 34–40, 1999), and effectiveness thereof is considered to be superior to that of thiazolidinedione type compounds. Compound A has no PPAR γ activating action which is the mode of action of thiazolidinedione type compounds. Therefore, Compound A has an apparently different action from that of thiazolidinedione type compounds, and is expected to achieve reduction of side effects.
